EP1283056B1 - Medizinische zusammensetzungen zur förderung der aktivierung der eingeweide - Google Patents

Medizinische zusammensetzungen zur förderung der aktivierung der eingeweide Download PDF

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Publication number
EP1283056B1
EP1283056B1 EP01925974A EP01925974A EP1283056B1 EP 1283056 B1 EP1283056 B1 EP 1283056B1 EP 01925974 A EP01925974 A EP 01925974A EP 01925974 A EP01925974 A EP 01925974A EP 1283056 B1 EP1283056 B1 EP 1283056B1
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group
constipation
pyridyl
compound
defecation
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EP1283056A4 (de
EP1283056A1 (de
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Masahiro Yasuda
Hitoshi Harada
Shuhei Miyazawa
Seiichi Kobayashi
Kokichi Harada
Takayuki Hida
Hisashi Shibata
Nobuyuki Yasuda
Osamu Asano
Yoshihiko Kotake
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Eisai Co Ltd
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Eisai Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/10—Laxatives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • H—ELECTRICITY
    • H04—ELECTRIC COMMUNICATION TECHNIQUE
    • H04B—TRANSMISSION
    • H04B10/00—Transmission systems employing electromagnetic waves other than radio-waves, e.g. infrared, visible or ultraviolet light, or employing corpuscular radiation, e.g. quantum communication
    • H04B10/11—Arrangements specific to free-space transmission, i.e. transmission through air or vacuum
    • H04B10/112—Line-of-sight transmission over an extended range

Definitions

  • the present invention relates to a novel pharmaceutical composition, and to a novel pyrimidine compound or a salt thereof, as well as uses of this compound for the manufacture of a pharmaceutical composition for promotion of defecation and for treating, preventing or improving constipation.
  • Constipation refers to a condition where defecation is difficult or rare, and this is a well-known disease.
  • Known constipation is divided mainly into e.g. functional constipation (acute constipation and various kinds of chronic constipation (for example, atonic constipation, spastic constipation, dyschezia, rectal constipation, chemically inducible constipation etc.)), organic constipation, enteroparalytic ileus, IBS, constipation accompanying IBS, constipation accompanying congenital digestive tract dysfunction, constipation accompanying ileus etc.
  • functional constipation acute constipation and various kinds of chronic constipation (for example, atonic constipation, spastic constipation, dyschezia, rectal constipation, chemically inducible constipation etc.)
  • organic constipation enteroparalytic ileus
  • IBS constipation accompanying IBS
  • constipation accompanying congenital digestive tract dysfunction constipation accompanying ileus etc
  • constipation is a serious problem in the fields of nursing and clinical and medical cure.
  • patients with constipation for example, atonic constipation
  • Another factor is an increase in diseases readily causing a reduction in the motility function of digestive tracts.
  • diabetes is one of serious diseases, and is problematic as complications to cause a rapid increase in patients with constipation.
  • Adenosine is an important regulatory factor involved in many intracellular metabolisms such as regulation of energy levels and cAMP levels in the living body, opening and closing calcium channels, and inflow of calcium ions into cells, and its interaction with adenosine receptors on the surface of a cell is essential for exhibiting these physiological activities.
  • receptor subtypes A 1 , A 2a , A 2b , A 3 .
  • the A 1 receptor occurs relatively abundantly in the heart, aorta, bladder etc., but hardly occurs in the jejunum and in the proximal colon
  • the A 2a receptor is distributed relatively abundantly in the eyeballs, skeletal muscles etc.
  • the A 2b receptor in the proximal colon, eyeballs, lung etc.
  • the A 3 receptor in the spleen, uterus, prostate etc.
  • Adenosine is involved in various physiological functions such as platelet agglutination, heart beat, contraction of smooth muscles, inflammations, release of neurotransmitters, neurotransmission, release of hormones, cellular differentiation, growth of cells, death of cells, biosynthesis of DNA, etc., thus suggesting the relationship thereof with central nerve diseases, cardiovascular diseases, inflammatory diseases, respiratory diseases, immune diseases etc., so usefulness of adenosine receptor agonists/antagonists against these diseases is expected.
  • the relationship between the adenosine receptors and the intestinal tracts has been reported in e.g. the followings 1) to 5):
  • the xanthine derivative not causing diarrhea described in WO94/16702 supra is reported to exhibit a defecation-promoting action based on an adenosine A 1 receptor antagonism via cholinergic nerves (Eur. J. Pharmacol., 264, 91 (1994)). Accordingly, it is considered as clinical significance if a strong defecation-promoting action can be exhibited via direct action on the digestive tracts.
  • the xanthine derivative exhibits a diuretic action based on an adenosine A 1 receptor antagonism (JP-A 3-173889), so its use as a defecation-promoting agent should be significantly limited.
  • the object of the present invention is to search for and find such medicaments.
  • the present inventors made further extensive study, and a result, they found a compound having an A 2 receptor antagonism, particularly a compound having an A 2b receptor antagonism, exhibits a gentle but strong defecation-promoting action without causing diarrhea, and the present invention was thereby completed.
  • the present invention relates to (14) a compound represented by the formula: (wherein A represents a phenyl group, pyridyl group, thienyl group or furyl group which may be substituted with one or two groups selected from a halogen atom, a hydroxyl group, a C 1-6 alkyl group, a C 1-6 alkoxy group and a C 1-6 alkoxy-carbonyl group; B represents a pyridyl group which may be substituted with one or more groups selected from a halogen atom, a hydroxyl group, a C 1-6 alkyl group and an amino group; R 1 represents a hydrogen atom, a morpholinyl group or a group represented by the formula -NR 1a R 1b (wherein R 1a and R 1b are the same as or different from each other and each represents a hydrogen atom, a C 1-6 alkyl group, a C 1-6 acyl group, a phenyl group or a C
  • the present invention relates to use of a compound represented by the formula (I) or (II) or a salt of them for producing a pharmaceutical composition for promoting defecation, and to use of a compound represented by the formula (I) or (II) or a salt of them for producing a pharmaceutical composition for treating, preventing or improving constipation.
  • the "defecation-promoting agent” refers to a pharmaceutical composition promoting physiological defecation.
  • the "constipation” refers to conditions where defecation is felt to be difficult or is rare, and includes various kinds of constipation such as functional constipation, organic constipation, enteroparalytic ileus, IBS, constipation accompanying IBS, constipation accompanying congenital digestive tract dysfunction and constipation accompanying ileus. Further the “constipation” also includes conditions with some sufferings and difficulties even in a small amount of defecation.
  • the functional constipation refers to acute constipation and various kinds of chronic constipation (for example, atonic constipation, spastic constipation, dyschezia, rectal constipation, chemically inducible constipation etc.).
  • the “compound” refers to both non-peptide compound and peptide compound.
  • the “compound” may form a salt, or may form either an anhydride or a hydrate.
  • the "salt” is not particularly limited insofar as it is a pharmacologically acceptable salt of the compound having an A 2 receptor antagonism or the compound having an A 2b receptor antagonism, and preferable examples thereof include 1) hydrohalogenic acid salts (for example, hydrofluoride, hydrochloride, hydrobromide and hydroiodide); 2) inorganic acid salts (for example, sulfate, nitrate, perchlorate, phosphate, carbonate and bicarbonate); 3) organic carboxylic acid salts (for example, acetate, oxalate, maleate, tartrate and fumarate); 4) organic sulfonic acid salts (for example, methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate and camphor sulfonate); 5) amino acid salts (for example, aspartate and glutacetate and
  • the “antagonism” refers to the action of inactivating by blocking the interaction of the adenosine receptor with its ligand (adenosine), that is, by blocking the binding of the ligand to the receptor.
  • the “compound having an antagonism” refers to a compound having the action of inactivating by blocking the binding of the ligand (adnosine) to the adenosine receptor.
  • Test Examples are described to demonstrate that the pharmaceutical composition according to the present invention is useful as a pharmaceutical composition (referred to hereinafter as "defecation-promoting agent") promoting defecation (Test Examples 1 to 3).
  • the compounds used in the test are compounds represented by the formulae: Compound I is a novel A 2b receptor antagonist (Example No. 3) found by the present inventors.
  • KF20274 and KW3902 are known as selective A 1 receptor antagonists, while KW6002 is known as a selective A 2a receptor antagonist.
  • the ability of these compounds to bind to adenosine receptor subtype and the inhibitory ability thereof are shown below (Table 6).
  • KF20274 was produced by a process described in J. Med. Chem., Vol.
  • Carbachol (Sigma) at each concentration diluted 100-fold was added accumulatively in a volume of 1/100 to the Magnus tube, and the change in the length of the colon tract was measured, and the length thereof in the absence of Carbachol was regarded as 0 % contraction, and the length thereof in the presence of 1.44 ⁇ M Carbachol was regarded as 100 % contraction. In the experiment, 3 samples were used.
  • 0.3 ⁇ M Carbachol and 1 ⁇ M NECA were successively added to the colon tract, and Compound I, KF20274 or KW6002 diluted 100-fold was accumulatively added in a volume of 1/100 to the Magnus tube, and the change in the length of the colon tract was measured. Assuming that the length thereof in the presence of 0.3 ⁇ M Carbachol and 1 ⁇ M NECA was regarded as 0 % contraction while the length thereof in the presence of 0.3 M Carbachol only was regarded as 100 % contraction, the contraction in the presence of each of the adenosine receptor antagonists was determined. In the experiment, 3 samples were used.
  • the present inventors examined and compared the action of the A 2b receptor antagonist (Compound I), the A 1 -selective antagonist or the A 2a -selective antagonist on defecation in rats.
  • 0.5 % (W/V) MC only was orally given to the control group.
  • the rats were returned to the cage provided with a new water-absorbing sheet of known weight, and 180 minutes after the administration, the fecal pellets on the water-absorbing sheet were recovered from each cage, and the external appearance was observed, and the number of fecal pellets was counted. The number of fecal pellets is expressed per each cage (Table 4).
  • the water-absorbing sheet was weighed, and the weight determined by subtracting the initial weight of the water-adsorbing sheet from the weight after the experiment was regarded as the volume of urine and expressed as the volume of urine per 100 g of the body weight (Table 4).
  • the A 1 -selective receptor antagonist KW3902 exhibits a defecation-promoting action, but this action can be seen to reach the maximum in a dose of 1 mg/kg. Further, the A 2a -selective receptor antagonist KW6002 had a low defecation-promoting action. On one hand, the A 2b receptor antagonist Compound I did not cause diarrhea and showed an evidently higher defecation-promoting action than the A 1 -selective antagonist KW3902 or the A 2a -selective antagonist KW6002.
  • Compound I is a compound also having an antagonistic, inhibitory action on A 1 receptor, but this strong defecation-promoting action cannot be elucidated in terms of the absorption or different dose of the compound having an antagonistic, inhibitory action on A 1 receptor. This is because compounds having an antagonistic, inhibitory action on A 1 receptor are well known to have a diuretic action (J. Pharmacol. Exp. Ther., 266, 200 (1993)), but the A 1 -selective antagonist KW3902 has a stronger diuretic action than Compound I, while its defecation-promoting action is weaker than Compound I. On the other hand, Compound I has a weaker diuretic action than the A 1 -selective antagonist KW3902, whereas its defecation-promoting action is stronger.
  • Table 4 shows that the action of Compound I cannot be elucidated only by the antagonistic action on A 1 receptor, and that the stronger defecating action was brought about by adding the antagonistic, inhibitory action on A 2b receptor.
  • Test Example 3 Contribution of inhibition of adenosine A 2b receptor to defecation-promoting action
  • Compound Dose KW6002 (1 mg/kg) The number of fecal pellets/3 rats Control - - 2.50 ⁇ 0.65 Compound 1 3 mg/kg - 34.00 ⁇ 1.00 KW3902 0 mg/kg + 7.00 ⁇ 1.58 1 mg/kg - 9.00 ⁇ 1.08 1 mg/kg + 18.25 ⁇ 1.49
  • the A 1 -selective antagonist KW3902 was administered in a dose enough to exhibit a diuretic action.
  • Table 5 when the A 1 -selective antagonist KW3902 and the A 2a -selective antagonist KW6002 were simultaneously administered, both their respective defecation-promoting actions were brought about. Accordingly, a compound having both an antagonistic action on A 1 receptor and an antagonistic action on A 2a receptor is considered to exhibit a stronger defecation-promoting action than by a single A 1 -selective antagonist. However, their action did not reach the defecation-promoting action of Compound I as the A 2b receptor antagonist. That is, the result in Table 5 shows that the contribution of A 2b receptor antagonism is very important for promotion of defecation.
  • a pharmaceutical preparation comprising the compound having an A 2b receptor antagonism or a salt thereof is useful as a defecation-promoting agent, and in particular a pharmaceutical preparation comprising the A 2b receptor antagonist is very useful.
  • the defecation-promoting agent of the invention is useful as an agent for treating, preventing or improving various kinds of constipation, and can exhibit an excellent effect as an agent for treating, preventing or improving for example functional constipation (acute constipation and various kinds of chronic constipation (for example, atonic constipation, spastic constipation, dyschezia, rectal constipation, chemically inducible constipation etc.)), organic constipation, enteroparalytic ileus, IBS, constipation accompanying IBS, constipation accompanying congenital digestive tract dysfunction, constipation accompanying ileus etc.
  • functional constipation acute constipation and various kinds of chronic constipation (for example, atonic constipation, spastic constipation, dyschezia, rectal constipation, chemically inducible constipation etc.)
  • organic constipation enteroparalytic ileus
  • IBS constipation accompanying IBS
  • constipation accompanying congenital digestive tract dysfunction constipation accompanying ile
  • defecation-promoting agent of the invention as a pharmaceutical preparation is very useful not only for treating, preventing or improving various kinds of constipation, but also as a chemical for evacuating intestinal tracts at the time of examination of digestive tracts or before and after an operation, as an aid for defecation after an operation, and as a chemical for promoting defecation after administering a contrast medium.
  • the ability of the compound to bind to and the ability thereof to inhibit each subtype of adenosine receptor was measured in a known method described below.
  • a human adenosine A 1 receptor cDNA was expressed in excess in CHOK1 cells, and this membrane sample was added at a protein concentration of 66.7 ⁇ g/ml to, and suspended in, 20 mM HEPES buffer, pH 7.4 (10 mM MgCl 2 , 100 mM NaCl). To 0.45 ml of this membrane sample suspension were added 0.025 ml of 60 nM tritium-labeled chlorocyclopentyl adenosine ( 3 H-CCPA, from NEN Ltd.) and 0.025 ml test compound.
  • 3 H-CCPA tritium-labeled chlorocyclopentyl adenosine
  • the total binding means 3 H-CCPA-bound radioactivity in the absence of the test compound; the non-specific binding means 3 H-CCPA-bound radioactivity in the presence of 100 ⁇ M RPIA ([R]-[1-methyl-2-phenylethyl] adenosine); and the binding in the presence of the test compound means 3 H-CCPA-bound radioactivity in the absence of the test compound at predetermined concentrations.
  • the inhibition constant (Ki value) in the table was determined from the formula of Cheng-Prusoff.
  • the total binding means 3 H-CGS21680-bound radioactivity in the absence of the test compound; the nonspecific binding means 3 H-CGS21680-bound radioactivity in the presence of 100 ⁇ M RPIA; and the binding in the presence of the test compound means 3 H-CGS21680-bound radioactivity in the absence of the test compound at predetermined concentrations.
  • the inhibition constant (Ki value) in the table was determined from the formula of Cheng-Prusoff.
  • CHOK1 cells where a human adenosine A 2b receptor had been expressed in excess were plated onto a 24-well plate at a density of 1.5 ⁇ 10 5 cells/well, cultured overnight, and used in the experiment.
  • the degree of inhibitory effect of the test compound on the amount of cAMP produced by stimulation with 30 nM 5'-N-ethylcarboxyamide adenosine (NECA from Sigma) was evaluated in terms of affinity for A 2b receptor. That is, the adhering cells were washed twice with 2 ml/well Krebs-Ringer buffer solution (containing 0.1% BSA; pH 7.4) and pre-incubated for 30 minutes in a volume of 0.5 ml/well.
  • a mixed solution containing NECA and the test compound was added in a volume of 0.1 ml/well in the presence of a phosphodiesterase inhibitor Ro-20-1724 (a product of RBI). After pre-incubation for 15 minutes, the reaction was terminated with 0.1 N HCl in a volume of 300 ⁇ l/well. Measurement of intracellular cAMP was carried out using a cAMP enzyme immunoassay kit produced by Amersham.
  • Inhibition (%) [1- ⁇ (amount of cAMP in the coexistence of NECA and the test compound-amount of cAMP in only the Krebs-Ringer buffer solution)/(amount of cAMP upon stimulation with NECA only-amount of cAMP in only the Krebs-Ringer buffer solution) ⁇ ] ⁇ 100
  • 8-phenyltheophylline (“8 - PT" in the table below) and 5- [6-amino-8-(3-fluorophenyl)-9H-9-purinyl]-1-methyl-1,2-dihydro-2-pyridinone (Compound II in the table below) disclosed in Example Number 5 described in WO 2001/2400 were as shown below.
  • 8-PT can be easily produced according to the description of Drug Development Research 47: 45-53 (1999), or is easily available as a commercial product (in this test, it was purchased from Sigma).
  • the present invention relates to a compound represented by the above formula (I) or (II) or a salt of them.
  • the compound is a novel pyrimidine compound found in the process of searching for the defecation-promoting pharmaceutical composition according to the present invention.
  • the compound is a compound exhibiting an excellent antagonistic action on adenosine A 2 receptor, particularly on adenosine A 2b receptor and having an excellent defecation-promoting action.
  • the structural formulae of the compounds represented by the formula (I) or (II) in the present invention or a salt thereof may, for convenience' sake, indicate a certain isomer, but this invention encompasses all possible isomers which can occur in the structures of the compounds, for example geometric isomer, optical isomer based on asymmetrical carbon, stereoisomer and tautomer, as well as a mixture of such isomers, so the compound of the invention may be any isomers or a mixture thereof without limitation to the formulae shown for convenience sake.
  • Compound (I) or (II) can have an intramolecular asymmetrical carbon to occur as optically active isomers or racemic modifications, and any of such compounds are included in this invention without limitation.
  • the compound of the invention may be in a single crystal form or a mixed crystal form without limitation.
  • Compound (I) or (II) in the invention or salts thereof may be anhydrides or hydrates, any of which fall under the claims in this specification.
  • metabolites formed by decomposition of Compound (I) or (II) in the living body, as well as prodrugs of Compound (I) or (II) or salts thereof also fall under the claims in this specification.
  • halogen atom used in this specification refers to an atom such as, for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, preferably a fluorine atom, a chlorine atom or a bromine atom, more preferably a fluorine atom or a chlorine atom, still more preferably a fluorine atom.
  • C 1-6 alkyl group used in this specification refers to an alkyl group containing 1 to 6 carbon groups, and examples thereof include linear or branched alkyl groups, preferably a methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, 2-ethylpropyl group, n-hexyl group, 1-methyl-2-ethylpropyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1-propylpropyl group, 1-methylbutyl group, 2-methylbutyl group, 1,1,-dimethylbutyl group, 1,2-dimethylbutyl group, 1,
  • C 1-6 alkoxy group used in this specification refers to an alkoxy group containing 1 to 6 carbon groups, and preferable examples include e.g. a methoxy group, ethoxy group, n-propoxy group, iso-propoxy group, sec-propoxy group, n-butoxy group, iso-butoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxy group, iso-pentyloxy group, sec-pentyloxy group, n-hexoxy group, iso-hexoxy group, 1,1-dimethylpropyloxy group, 1,2-dimethylpropoxy group, 2,2-dimethylpropyloxy group, 2-ethylpropoxy group, 1-methyl-2-ethylpropoxy group, 1-ethyl-2-methylpropoxy group, 1,1,2-trimethylpropoxy group, 1,1,2-trimethyl propoxy group, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 2,2-dimethylbutoxy group,
  • C 1-6 alkoxy-carbonyl group used in this specification refers to a carbonyl group to which a C 1-6 alkoxy group was bound, and examples thereof include a methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group, sec-propoxycarbonyl group, n-butoxycarbonyl group, iso-butoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group, n-pentyloxycarbonyl group, iso-pentyloxycarbonyl group, sec-pentyloxycarbonyl group, n-hexoxycarbonyl group, isohexoxycarbonyl group, 1,1-dimethylpropyloxycarbonyl group, 1,2-dimethylpropoxycarbonyl group, 2,2-dimethylpropoxycarbonyl group, 2-ethylpropoxycarbonyl group, 1-methyl-2-ethylpropoxycarbonyl group
  • acyl group used in this specification refers to an atomic group derived from a C 1-7 fatty acid carboxyl group by removing its OH group, and preferable groups include e.g. an acetyl group, propionyl group, butyroyl group etc.
  • C 1-6 alkyl sulfonyl group used in this specification refers to a sulfonyl group to which a C 1-6 alkyl group was bound, and preferable groups include a methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, isopropylsulfonyl group, n-butylsulfonyl group, isobutylsulfonyl group, sec-butylsulfonyl group, tert-butylsulfonyl group, n-pentylsulfonyl group, n-hexylsulfonyl group etc.
  • A represents a phenyl group; a pyridyl group, a thienyl group or a furyl group which may be substituted with one or two groups selected from a halogen atom, a hydroxyl group, a C 1-6 alkyl group, a C 1-6 alkoxy group and a C 1-6 alkoxy-carbonyl group, and preferable examples of the group A are not particularly limited.
  • the group A include a phenyl group, a pyridyl group, a thienyl group and a furyl group, each of which may be substituted with one to three groups selected from a fluorine atom, a chlorine atom, a hydroxyl group, a methyl group, an ethyl group, a methoxy group and an ethoxy group.
  • Still more preferable groups include 1) a phenyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-furyl group, 3-furyl group, 2-thienyl group and 3-thienyl group, each of which is unsubstituted, and 2) a phenyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-furyl group, 3-furyl group, 2-thienyl group, 3-thienyl group etc., each of which is substituted with one to three groups selected from a fluorine atom, chlorine atom, hydroxyl group, methyl group, ethyl group, methoxy group and ethoxy group.
  • B represents a pyridyl group which may be substituted with one or more groups selected from a halogen atom, a hydroxyl group, a C 1-6 alkyl group and an amino group, and preferable examples of the group B are not particularly limited. More preferable examples of the group B is 1) an unsubstituted 4-pyridyl 'group or 2) a 4-pyridyl group which is substituted with one to three groups selected from a fluorine atom, a chlorine atom, a hydroxyl group, a methyl group, an ethyl group, a n-propyl group, an iso-propyl group and an amino group.
  • B' represents a 1,2-dihydro-2-pyridinone-4 -yl group which may be substituted with one or more groups selected from a halogen atom, a hydroxyl group, a C 1-6 alkyl group and an amino group
  • preferable examples of the group B' are not particularly limited, and more preferable examples include 1) an unsubstituted 1,2-dihydro-2-pyridinone-4-yl group, 2) an 1,2-dihydro-2-pyridinone-4-yl group which is substituted with one to two groups selected from a fluorine atom, chlorine atom, hydroxyl group, methyl group, ethyl group, n-propyl group, iso-propyl group and amino group, and a still further preferable group is an unsubstituted 1.2-dihydro-2-pyridinone-4-yl group.
  • R 1 represents a hydrogen atom, a morpholinyl group, or a group represented by the formula - NR 1a R 1b (wherein R 1a and R 1b are the same as or different from each other and each represents a hydrogen atom, a C 1-6 alkyl group, a C 1-6 acyl group, a phenyl group or a C 1-6 alkyl sulfonyl group) , and 1) a hydrogen atom, 2) a 4-morpholinyl group, 3) an amino group, 4) a C 1-6 alkylamino group (for example, a methylamino group, ethylamino group, n-propylamino group, iso-propylamino group etc.), 5) an N,N-diC 1-6 alkyl amino group (for example, a dimethylamino group, diethylamino group, etc.), 6) a C 1-6 acyl amino
  • R 2 represents a hydrogen atom or a group represented by the formula -NR 2a R 2b (wherein R 2a and R 2b are the same as or different from each other and each represents a hydrogen atom or a C 1-6 alkyl group, and more preferable groups include a hydrogen atom, an amino group, a methyl amino group, an ethyl amino group, an N,N-dimethylamino group, an N,N-methylethylamino group, etc.
  • Compound (I) or (II) include the following compounds:
  • room temperature refers usually to 10 to 35°C.
  • A represents a phenyl group, pyridyl group, thienyl group or furyl group which may be substituted with one or two groups selected from a halogen atom, a hydroxyl group, a C 1-6 alkyl group, a C 1-6 alkoxy group and a C 1-6 alkoxy-carbonyl group
  • B represents a pyridyl group which may be substituted with one or more groups selected from a halogen atom, a hydroxyl group, a C 1-6 alkyl group and an amino group
  • X represents a C 1-8 alkyl group.
  • Step A1 is a step of producing 1,2-biaryl-1- ethanone compound (3) which is an intermediate for production of the compound represented by the above formula (I) in this invention. That is, Compound (3) is obtained through condensation via alcohol elimination by reacting an aromatic carboxylate (1) with 4-methylpyridine derivative (2) in a solvent in the presence of a base.
  • the base used is varied depending on the starting materials, reagents, solvent etc. used, and is not particularly limited insofar as the reaction is not inhibited, and preferable examples of the base include secondary amine metal salts such as lithium bis(trimethylsilyl)amide and lithium diisopropylamide.
  • the solvent used is varied depending on the starting materials and reagents used, and is not particularly limited insofar as the reaction is not inhibited and the starting materials are dissolved to a certain degree, and preferable examples of the solvent include ethers such as tetrahydrofuran, dioxane, dimethyxyethane and diethylene glycol etc.
  • the reaction temperature is preferably -78°C to room temperature, more preferably in the vicinity of 0°C. wherein A and the ring B have the same meanings as defined above; and Me is a methyl group.
  • N,N-dimethylformamide dimethyl acetal is allowed to act on the active methylene of Compound (3) produced in Production Method A, whereby 3-(dimethylamino)-2-propene-1-one compound (4) as an intermediate for production of the compound represented by the above formula (I) in this invention can be produced (step B1).
  • This reaction is carried out preferably in the absence of a solvent, but the reaction may be carried out after diluting with a solvent not inhibiting the reaction and dissolving the starting materials to a certain degree, for example, N,N-dimethylformamide, tetrahydrofuran, dioxane, N-methyl pyrrolidone, benzene, toluene etc.
  • the solvent used herein is varied depending on the starting materials, reagents etc. used, and is not particularly limited.
  • the reaction temperature is preferably room temperature to 120°C, more preferably about 100°C.
  • R 1 represents a hydrogen atom, a morpholinyl group or a group represented by the formula -NR 1a R 1b (wherein R 1a and R 1b are the same as or different from each other and each represents a hydrogen atom, a C 1-6 alkyl group, a C 1-6 acyl group, a phenyl group or a C 1-6 alkylsulfonyl group).
  • Formamidine or guanidine derivative (5) is reacted in the presence of a base with the 3-(dimethylamino)-2-propene-1-one compound (4) obtained in Production Method B, whereby Compound (6) in this invention can be produced (step C1).
  • the guanine derivative (5) used is not only easily commercially available but can also be produced by a known method described in e.g. J. Org. Chem., 57, 2497-2502 (1992) or its analogous method.
  • the base used is varied depending on the starting materials, reagents, solvent etc.
  • reaction is carried out preferably in a solvent not inhibiting the reaction and dissolving the starting materials and base to a certain degree, for example in N,N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, methanol, ethanol etc., but it varies depending on the starting materials, reagents etc. used, and is not particularly limited.
  • alkali metal carbonates for example, potassium carbonate, sodium carbonate, etc.
  • alkali metal alkoxides for example, sodium methoxide, sodium ethoxide, potassium tert-butoxide etc.
  • This reaction is carried out preferably in a solvent not inhibiting the reaction and dissolving the starting materials and base to a certain degree, for example in N,N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, methanol, ethanol etc., but it varies depending on the starting materials, reagents etc. used, and is not particularly limited.
  • reaction temperature is preferably room temperature to 120°C, more preferably about 70°C.
  • A, ring B, and R 1 have the same meanings as def ined above.
  • Compound (9) in this invention can be obtained by dehydration condensation of aryl aldehyde with aryl acetonitrile (7) in the presence of a base, to produce 2,3-biaryl-2-propenenitrile (8) (step D1), then allowing formanidine or guanidine derivative to react on the nitrile compound (8) in the presence of a base and converting the product into an aromatic derivative by an oxidizing agent (step D2).
  • step D1 the formamidine or guanidine derivative may be coexistent from the start in the reaction, and the 2,3-biaryl-2-propenenitrile (8) can be converted without isolation into its corresponding aromatic compound by an oxidizing agent, to produce the pyrimidine derivative (9) in the invention.
  • a and the ring B have the same meanings as defined above, and R 3 represents a hydrogen atom or a C 1-6 alkyl group.
  • Step E1 is a step where a carboxylic anhydride is allowed to act on Compound (10) under acidic conditions to acrylate the amino group thereof, whereby the acyl derivative (11) according to the present invention is produced.
  • the starting compound (10) can be produced in Production Method C above, and corresponds to Compound (6) wherein R 1 is an amino group.
  • Step E1 is carried out preferably in the absence of a solvent, but may be conducted after dilution with a solvent.
  • a solvent is varied depending on the starting material, reagents, etc. used, and is not particularly limited insofar as it dissolves the staring materials without inhibiting the reaction, and preferable examples are N,N-dimethylformamide, tetrahydrofuran, dioxane, N-methyl pyrrolidone, benzene, toluene, etc.
  • the acid used is varied depending on the starting materials, reagents, solvent, etc.
  • reaction temperature is preferably room temperature to 120°C, more preferably about 90°C.
  • a and the ring B have the same meanings as defined above, and R 4 represents a hydrogen atom or a C 1-6 alkyl group.
  • the sulfonamide derivative (13) in this invention can be produced by allowing sulfonyl chloride under basic conditions to act on Compound (12) as the starting material (that is, Compound (11) wherein R 3 is a methyl group) which can be produced by Production Method E above, thus sulfonylating Compound (12), and then removing the acyl group under acidic conditions (step F1).
  • the base used in the sulfonylation reaction is varied depending on the starting materials, reagents, solvent, etc. used, and is not particularly limited insofar as the reaction is not inhibited, and preferable examples are sodium hydride, etc.
  • the solvent used in the sulfonylation is varied depending on the starting materials, reagents, etc.
  • reaction temperature is preferably -10°C to room temperature.
  • the acid used in the de-acetylation reaction in step F1 is varied depending on the starting materials, reagents, solvent etc. used, and is not particularly limited insofar as the reaction is not inhibited, and a preferable example is hydrochloric acid or the like.
  • the solvent used in the reaction is varied depending on the starting materials, reagents, etc.
  • the reaction temperature is preferably room temperature to 100°C. wherein A and R 1 have the same meanings as defined above.
  • the compound represented by the formula (II) in the present invention can be produced, for example, in the step G1.
  • Compound (14) as the starting material can be produced by Production Method C above.
  • the pyridone derivative (15) according to the present invention can be produced by hydrolyzing the according (14) under acidic conditions.
  • the acid used is varied depending on the starting materials, reagents, solvent, etc. used, and is not particularly limited insofar as the reaction is not inhibited, and preferable examples are hydrochloric acid, hydrobromic acid, sulfuric acid, etc.
  • This reaction is carried out preferably in water, and the reaction temperature is usually room temperature to about 120°C, preferably 100°C. wherein A and R 1 have the same meanings as defined above.
  • Compound (16) according to the present invention can be produced by allowing ammonia to act on Compound (14) which can be produced by Production Method C above to substitute the fluorine atom by an amino group (step H1).
  • An ammonia gas saturated in a suitable solvent such as ethanol is used as the reagent in this reaction.
  • the reaction solution is sealed in e.g. an autoclave and heated to about 150°C.
  • the starting compound in production of Compound (I) or (II) in the present invention may be in the form of a salt or a hydrate and is not particularly limited insofar as the reaction is not inhibited. Further, when Compound (I) or (II) in the invention is obtained in a free form, it can be converted in a usual manner into a salt form which Compound (I) or (III) may form.
  • the resultant isomers for example, geometric isomer, optical isomer based on asymmetric carbon, stereoisomer, tautomer etc.
  • Compound (I) or (II) of the present invention can be purified and isolated by usual separating means, for example recrystallization, diastereomer salt method, enzyme fractionation method, and various kinds of chromatography (for example, thin-layer chromatography, column chromatography, gas chromatography etc.).
  • the pharmaceutical composition of the invention can be manufactured by a conventional method, and preferable preparation forms include tablets, powders, fine granules, granules, coated tablets, capsules, syrups, troches, inhalations, suppositories, injections, ointments, eye ointments, eye drops, nose drops, ear drops, poultices, lotions and the like.
  • Ordinarily used fillers, binders, disintegrating agents, lubricants, coloring agents, flavoring agents, and as necessity, stabilizers, emulsifiers, absorption promoters, surfactants, pH adjusters, preservatives and antioxidants can be used in pharmaceutical manufacturing, and ingredients used generally as starting materials for pharmaceutical preparations can be blended in a usual manner for manufacturing.
  • ingredients include e.g. (1) animal and vegetable oils such as soybean oil, tallow and synthetic glyceride; (2) hydrocarbons such as liquid paraffin, squalane and solid paraffin; (3) ester oils such as octyldodecyl myristate and isopropyl myristate; (4) higher alcohols such as cetostearyl alcohol and behenyl alcohol; (5) silicon resin; (6) silicon oil; (7) surfactants such as polyoxyethylene fatty ester, sorbitan fatty ester, glycerin fatty ester, polyoxyethylene sorbitan fatty ester, polyoxyethylene hardened castor oil and polyoxyethylene polyoxypropylene block copolymer; (8) water-soluble polymers such as hydroethyl cellulose, polyacrylic acid, carboxyvinyl polymer, polyethylene glycol, polyvinyl pyrrolidone and methyl cellulose; (9) lower alcohols such as ethanol and isopropanol; (10) polyvalent alcohols such
  • the fillers include e.g. lactose, corn starch, white sugar, glucose, mannitol, sorbitol, crystalline cellulose, silicon dioxide etc.; 2) the binders include e.g. polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, arabic gum, tragacanth, gelatin, shellac, hydroxy propyl cellulose, hydroxy propylmethyl cellulose, polyvinyl pyrrolidone, polypropylene glycol-polyoxyethylene block polymer, meglumine, calcium citrate, dextrin, pectin etc.; 3) the disintegrating agents include e.g.
  • the lubricants include e.g. magnesium stearate, talc, polyethylene glycol, silica, hardened vegetable oil etc.;
  • the coloring agents include e.g. those coloring agents approved to be added to pharmaceutical preparations;
  • the flavoring agents include cocoa powder, menthol, aromatic powder, peppermint oil, borneol, cinnamon powder etc.;
  • the antioxidants include those approved to be added to pharmaceutical preparations, such as ascorbic acid and ⁇ -tocopherol.
  • the oral preparation is produced by mixing the active ingredient with fillers and if necessary with a binder, a disintegrating agent, a lubricant, a coloring agent, a flavoring agent etc., and then forming it in a usual manner into powders, fine granules, granules, tablets, coated tablets, capsules, etc. 2) The tablets and granules may be coated with a sugar or gelatin coating or if necessary with another suitable coating. 3) The liquid preparations such as syrups, injections and eye drops are prepared by mixing the active agent with a pH adjuster, a solubilizer and an isotonizing agent etc., and with a solubilizing aid, a stabilizer, a buffer, a suspension agent, an antioxidant etc.
  • the liquid preparation may be formed into a freeze-dried product and the injection can be administered intravenously, subcutaneously or intramuscularly.
  • the suspension agent include methyl cellulose, Polysorbate 80, hydroxyethyl cellulose, arabic gum, tragacanth powder, sodium carboxymethyl cellulose, polyoxyethylene sorbitan monolaurate etc.
  • the solubilizing aid include polyoxyethylene hardened castor oil, Polysorbate 80, nicotinamide, polyoxyethylene sorbitan monolaurate etc.
  • preferable examples of the stabilizer include sodium sulfite, sodium metasulfite, ether etc.
  • preferable examples of the preservative include methyl p-oxybenzoate, ethyl p-oxybenzoate, sorbic acid, phenol, cresol, chlorocresol etc.
  • the agent for external application can be produced in any conventional method. That is, the starting base material can make use of various starting materials ordinarily used in pharmaceutical preparations, non-pharmaceutical preparations, cosmetics, etc.
  • the material includes animal and vegetable oils, mineral oil, ester oil, waxes, higher alcohols, fatty acids, silicon oil, surfactants, phospholipids, alcohols, polyvalent alcohols, water-soluble polymers, clay minerals, pure water etc. If necessary, a pH adjuster, an antioxidant, a chelating agent, a preservative, a coloring agent, a perfume etc. can further be added.
  • ingredients having a differentiation-inducing action a blood-stream promoting agent, a sterilizer, an antiinflammatory agent, a cell activator, vitamins, amino acids, a humectant, a keratin solubilizer etc. can also be incorporated as necessity.
  • the dose of the pharmaceutical composition or compound according to the present invention is varied depending on severity of symptoms, age, sex, body weight, administration form, type of salt, chemical sensitivity, specific type of disease etc., it is given daily in one portion or in divided portions into an adult in a dose of usually about 30 ⁇ g to 10 g, preferably 100 ⁇ g to 5 g, more preferably 100 ⁇ g to 100 mg for oral administration, or about 30 ⁇ g to 1 g, preferably 100 ⁇ g to 500 mg, more preferably 100 ⁇ g to 30 mg for injection.
  • a novel pharmaceutical composition promoting defecation there can be provided a novel pharmaceutical composition promoting defecation.
  • the defecation-promoting agent according to the present invention is useful as a pharmaceutical preparation promoting physiological defecation.
  • a novel pyrimidine compound and a salt thereof there can also be provided.
  • the compound or a salt thereof is useful as a pharmaceutical preparation exhibiting an excellent antagonistic action on adenosine A 2 receptor, particularly on A 2b receptor, and simultaneously promoting defecation.
  • the defecation-promoting pharmaceutical composition according to the present invention and the compound of the present invention are useful as an agent for treating, preventing or improving various kinds of constipation, for example functional constipation (acute constipation and various kinds of chronic constipation (for example, atonic constipation, spastic constipation, dyschezia, rectal constipation, chemically inducible constipation etc.)), organic constipation, enteroparalytic ileus, IBS, constipation accompanying IBS, constipation accompanying congenital digestive tract dysfunction, constipation accompanying ileus etc.
  • functional constipation acute constipation and various kinds of chronic constipation (for example, atonic constipation, spastic constipation, dyschezia, rectal constipation, chemically inducible constipation etc.)
  • organic constipation enteroparalytic ileus
  • IBS constipation accompanying IBS
  • constipation accompanying congenital digestive tract dysfunction constipation accompanying ileus etc.
  • defecation-promoting agent according to the present invention as a pharmaceutical preparation is not limited to the treatment, prevention or improvement of various kinds of constipation, but it is also useful as a chemical for evacuating intestinal tracts at the time of examination of digestive tracts or before and after an operation, as an aid for defecation after an operation, as a chemical for promotion of defecation after administering a contrast medium, and as a defecation-promoting agent when the patient is hypertensive or has a dangerous of cerebral apoplexy, cerebral infarction, cardiac infarction, etc.
  • Lithium bis(trimethylsilyl)amide (100 mL, 100 mmol) was added dropwise over 1 hour to a solution of 4-picoline (4.6 g, 49.4 mmol) and ethyl 2-furancarboxylate (7.7 g, 54.9 mmol) in tetrahydrofuran (40 mL) at 0°C in a nitrogen atmosphere, followed by stirring as such for 2 hours.
  • Hexane 140 mL was added to the reaction solution, and the resulting crystals were collected by filtration. The resulting crystals were dissolved in ethyl acetate and an aqueous saturated ammonium chloride solution.
  • N,N-dimethylformamide dimethyl acetal (5 mL) was added to 1- (2-furyl)-2-(4-pyridyl)-1-ethanone (2.0 g, 10.7 mmol) and stirred at 100°C for 2 hours. After cooling as it was, the reacton mixture was diluted with ethyl acetate and an aqueous saturated ammonium chloride solution. The aqueous layer was extracted with ethyl acetate ( ⁇ 6). The combined organic layer was dried over anhydrous sodium sulfate and concentrated, to give the title compound (2.5 g, 97 %) as a reddish brown oil.
  • 1 H NMR 400 MHz, DMSO- d 6 ) ⁇ ppm; 2.
  • Tetrahydrofuran (200 mL) and activated manganese dioxide (30.0 g) were added to the residue, followed by heating under reflux for 2.5 hours. After cooling as it was, the manganese dioxide was filtered through Celite, and washed with tetrahydrofuran. The collected filtrate was concentrated, and then methanol was added to the residues. The resulting precipitates were collected by filtration and washed with methanol, to give the title compound (3.48 g, 21 %) as a pale brown solid.
  • 1 H NMR (400 MHz, DMSO- d 6 ) ⁇ ppm; 5.88 (2H, br s), 6.15 (2H, br s), 6.18 (1H, d, J 3.2 Hz), 6.
  • the defecation-promoting action of the adenosine A 2b receptor-inhibiting compound which was identified by measuring the binding ability and inhibitory ability thereof to the adenosine receptor in the above method, a salt thereof, a hydrate of them, or a pharmaceutical composition containing it can be evaluated on the basis of the method described in this specification.
  • Example 1 The defecation-promoting action of the title compound in Example 1 is shown below.
  • the defecation-promoting action of the title compound in Example 3 is as shown in the above tables.
  • Compound Dose The number of fecal pellets/3 rats Control - 4.67 ⁇ 1.26 Example 1 3 mg/kg 14.83 ⁇ 1.82 10 mg/kg 23.17 ⁇ 2.94

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Claims (15)

  1. Verbindung mit der Formel:
    Figure 00840001
    [worin A eine Phenylgruppe, Pyridylgruppe, Thienylgruppe oder Furylgruppe bedeutet, die mit einer oder zwei Gruppen substituiert sein kann, die ausgewählt sind aus einem Halogenatom, einer Hydroxylgruppe, einer C1-6-Alkylgruppe, einer C1-6-Alkoxygruppe und einer C1-6-Alkoxycarbonylgruppe; B eine Pyridylgruppe bedeutet, die mit einer oder mehreren Gruppen substituiert sein kann, die ausgewählt sind aus einem Halogenatom, einer Hydroxylgruppe, einer C1-6-Alkylgruppe und einer Aminogruppe; R1 ein Wasserstoffatom, eine Morpholinylgruppe oder eine Gruppe mit der Formel - NR1aR1b (worin R1a und R1b gleich oder verschieden voneinander sind und jeweils ein Wasserstoffatom, eine C1-6-Alkylgruppe, eine C1-6-Acylgruppe, eine Phenylgruppe oder eine C1-6-Alkylsulfonylgruppe bedeuten) bedeutet; und R2 ein Wasserstoffatom oder eine Gruppe mit der Formel -NR2aR2b (worin R2a und R2b gleich oder verschieden voneinander sind und jeweils ein Wasserstoffatom oder eine C1-6-Alkylgruppe bedeuten) bedeutet,
    mit der Massgabe, dass in der obigen Definition die Fälle (i), wo A eine 4-Fluorphenylgruppe ist; B eine 4-Pyridylgruppe ist; R1 eine Aminogruppe ist; und R2 ein Wasserstoffatom ist, und (ii), wo A eine 4-Fluorphenylgruppe ist; B eine 4-Pyridylgruppe ist; R1 eine Acetamidgruppe ist; und R2 ein Wasserstoffatom ist, ausgeschlossen sind] oder ein Salz davon.
  2. Verbindung mit der Formel:
    Figure 00850001
    (worin A, R1 und R2 dieselben Bedeutungen wie in Anspruch 1 definiert haben; und B' eine 1,2-Dihydro-2-pyridinon-4-yl-Gruppe bedeutet, welche mit einer oder mehreren Gruppen substituiert sein kann, die ausgewählt sind aus einem Halogenatom, einer Hydroxylgruppe, einer C1-6-Alkylgruppe und einer Aminogruppe) oder ein Salz davon.
  3. Pharmazeutische Zusammensetzung, welche die Verbindung gemäss Anspruch 1 oder 2 oder ein Salz von diesen umfasst.
  4. Zusammensetzung gemäss Anspruch 3, welche ein Adenosin A2b-Rezeptorantagonist ist.
  5. Zusammensetzung gemäss Anspruch 3, welche ein stuhlgangförderndes Mittel ist.
  6. Zusammensetzung gemäss Anspruch 3, welche ein Mittel zur Behandlung, Vorbeugung oder Verbesserung von Verstopfung ist.
  7. Zusammensetzung gemäss Anspruch 3, welche ein Mittel zur Behandlung, Vorbeugung oder Verbesserung von funktioneller Verstopfung ist.
  8. Zusammensetzung gemäss Anspruch 7, wobei die funktionelle Verstopfung spastische Verstopfung oder atonische Verstopfung ist.
  9. Zusammensetzung gemäss Anspruch 3, welche ein Mittel zur Behandlung, Vorbeugung oder Verbesserung von Reizkolon oder Verstopfung, welche das Reizkolon begleitet, ist.
  10. Zusammensetzung gemäss Anspruch 3, welche ein Mittel zur Behandlung, Vorbeugung oder Verbesserung organischer Verstopfung, Verstopfung, die enteroparalytischen Ileus begleitet, Verstopfung, die kongenitale Verdauungstraktdysfunktion begleitet, oder Verstopfung, die Ileus begleitet, ist.
  11. Zusammensetzung gemäss Anspruch 3, welche zur Entleerung des Darmtrakts zum Zeitpunkt der Untersuchung des Verdauungstrakts oder vor und nach einer Operation dient.
  12. Verwendung der in Anspruch 1 oder 2 beschriebenen Verbindung oder eines Salzes davon zur Herstellung eines stuhlgangfördernden Mittels.
  13. Verwendung der in Anspruch 1 oder 2 beschriebenen Verbindung oder eines Salzes davon zur Herstellung eines Mittels zur Behandlung, Vorbeugung oder Verbesserung von Verstopfung.
  14. Verwendung einer pharmakologisch wirksamen Menge der in Anspruch 1 oder 2 beschriebenen Verbindung oder eines Salzes davon zur Herstellung einer pharmazeutischen Zusammensetzung zur Förderung von Stuhlgang.
  15. Verwendung einer pharmakologisch wirksamen Menge der in Anspruch 1 oder 2 beschriebenen Verbindung oder eines Salzes davon zur Herstellung einer pharmazeutischen Zusammensetzung zur Behandlung, Vorbeugung oder Verbesserung von Verstopfung.
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US7189717B2 (en) 2007-03-13
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